Glioblastoma-instructed astrocytes suppress tumour-specific T cell immunity
Bibliographic record
Abstract
Abstract Introduction Glioblastoma (GBM) is an aggressive primary brain cancer with minimal response to current therapies. An immunosuppressive tumor microenvironment limits immunotherapeutic efficacy. Astrocytes are the most abundant glial cells in the central nervous system and play important roles in locally regulating immune responses. However, in the context of GBM little is known about mechanisms regulating astrocytes or their roles in the modulating anti-tumor immune responses. Methods We used single-cell and bulk RNA sequencing of human GBM specimens and murine preclinical models, multiplexed immunofluorescence, in vivo cell-specific genetic perturbations via CRISPR and in vitro mouse and human experimental astrocyte and GBM models to address this gap in knowledge. Results We identified an astrocyte subset which limits T cell anti-tumor responses by inducing T cell apoptosis via TRAIL, a death receptor ligand. Further, we identified IL-11 produced by GBM cells as a driver of STAT3 signaling in this astrocyte subset and a regulator of TRAIL expression. Astrocyte STAT3 signaling and TRAIL expression were correlated with more aggressive tumor progression and decreased survival in GBM patients. Following in vivo genetic inactivation of TRAIL or of the IL-11 receptor in astrocytes we observed extended survival in GBM mouse models, alongside enhanced T cell and macrophage responses. Finally, we engineered an oncolytic HSV-1 virus to express a TRAIL-blocking single-chain antibody in the tumor microenvironment. TRAIL blockade enhanced therapeutic effect of oncolytic viruses, extended survival and enhanced tumor-specific immunity in preclinical models of GBM. Conclusion In summary, we establish that IL-11—STAT3 signaling drives astrocytes to suppress GBM-specific immune responses by inducing TRAIL-dependent T cell apoptosis, and engineered a therapeutic strategy leveraging oncolytic viruses as delivery vectors to target this mechanism of astrocyte-driven immunosuppression in the tumor microenvironment. Funding Source This work was supported by grants NS102807, ES02530, ES029136, AI126880 from the NIH; RG4111A1 and JF2161-A-5 from the NMSS; RSG-14-198-01-LIB from the American Cancer Society; and PA-1604-08459 from the International Progressive MS Alliance. This work was further supported by a scholarship from the German Academic Exchange Service (DAAD). Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".